tbuckley/cabot-search huggingface dataset:
Cross-species efficacy of enzyme replacement therapy for CLN1 disease in mice and sheep
Authors: Hemanth R. Nelvagal, Samantha L. Eaton, Sophie H. Wang, Elizabeth M. Eultgen, Keigo Takahashi, Steven Q. Le, Rachel Nesbitt, Joshua T. Dearborn, Nicholas Siano, Ana C. Puhl, Patricia I. Dickson, Gerard Thompson, Fraser Murdoch, Paul M. Brennan, Mark Gray, Stephen N. Greenhalgh, Peter Tennant, Rachael Gregson, Eddie Clutton, James Nixon, Chris Proudfoot, Stefano Guido, Simon G. Lillico, C. Bruce A. Whitelaw, Jui-Yun Lu, Sandra L. Hofmann, Sean Ekins, Mark S. Sands, Thomas M. Wishart, Jonathan D. Cooper
Journal: Journal of Clinical Investigation (2022)

CLN1 disease, also called infantile neuronal ceroid lipofuscinosis (NCL) or infantile Batten disease, is a fatal neurodegenerative lysosomal storage disorder resulting from mutations in the CLN1 gene encoding the soluble lysosomal enzyme palmitoyl-protein thioesterase 1 (PPT1). Therapies for CLN1 disease have proven challenging because of the aggressive disease course and the need to treat widespread areas of the brain and spinal cord. Indeed, gene therapy has proven less effective for CLN1 disease than for other similar lysosomal enzyme deficiencies. We therefore tested the efficacy of enzyme replacement therapy (ERT) by administering monthly infusions of recombinant human PPT1 (rhPPT1) to PPT1-deficient mice (Cln1–/–) and CLN1R151X sheep to assess how to potentially scale up for translation. In Cln1–/– mice, intracerebrovascular (i.c.v.) rhPPT1 delivery was the most effective route of administration, resulting in therapeutically relevant CNS levels of PPT1 activity. rhPPT1-treated mice had improved motor function, reduced disease-associated pathology, and diminished neuronal loss. In CLN1R151X sheep, i.c.v. infusions resulted in widespread rhPPT1 distribution and positive treatment effects measured by quantitative structural MRI and neuropathology. This study demonstrates the feasibility and therapeutic efficacy of i.c.v. rhPPT1 ERT. These findings represent a key step toward clinical testing of ERT in children with CLN1 disease and highlight the importance of a cross-species approach to developing a successful treatment strategy.
Experimenters’ sex modulates mouse behaviors and neural responses to ketamine via corticotropin releasing factor
Authors: Polymnia Georgiou, Panos Zanos, Ta-Chung M. Mou, Xiaoxian An, Danielle M. Gerhard, Dilyan I. Dryanovski, Liam E. Potter, Jaclyn N. Highland, Carleigh E. Jenne, Brent W. Stewart, Katherine J. Pultorak, Peixiong Yuan, Chris F. Powels, Jacqueline Lovett, Edna F. R. Pereira, Sarah M. Clark, Leonardo H. Tonelli, Ruin Moaddel, Carlos A. Zarate, Ronald S. Duman, Scott M. Thompson, Todd D. Gould
Journal: Nature Neuroscience (2022)
Predicting cognitive decline in Parkinson’s disease using FDG-PET–based supervised learning
Authors: Samuel Booth, Kye Won Park, Chong Sik Lee, Ji Hyun Ko
Journal: Journal of Clinical Investigation (2022)

Background. Cognitive impairment is a common symptom of Parkinson's disease (PD) that increases in risk and severity as the disease progresses. An accurate prediction of the risk of progression from the mild cognitive impairment (MCI) stage to the dementia (PDD) stage is an unmet clinical need.
Androgen Receptor Signaling Inhibitors in Addition to Docetaxel with Androgen Deprivation Therapy for Metastatic Hormone-sensitive Prostate Cancer: A Systematic Review and Meta-analysis
Authors: Takafumi Yanagisawa, Pawel Rajwa, Constance Thibault, Giorgio Gandaglia, Keiichiro Mori, Tatsushi Kawada, Wataru Fukuokaya, Sung Ryul Shim, Hadi Mostafaei, Reza Sari Motlagh, Fahad Quhal, Ekaterina Laukhtina, Maximilian Pallauf, Benjamin Pradere, Takahiro Kimura, Shin Egawa, Shahrokh F. Shariat
Journal: European Urology (2022)

Recent randomized controlled trials (RCTs) examined the role of adding androgen receptor signaling inhibitors (ARSIs), including abiraterone acetate (ABI), apalutamide, darolutamide (DAR), and enzalutamide (ENZ), to docetaxel (DOC) and androgen deprivation therapy (ADT) in patients with metastatic hormone-sensitive prostate cancer (mHSPC). To analyze the oncologic benefit of triplet combination therapies using ARSI + DOC + ADT, and comparing them with available treatment regimens in patients with mHSPC. Three databases and meetings abstracts were queried in April 2022 for RCTs analyzing patients treated with first-line combination systemic therapy for mHSPC. The primary interests of measure were overall survival (OS) and progression-free survival (PFS). Subgroup analyses were conducted to assess the differential outcomes in patients with low- and high-volume disease as well as de novo and metachronous metastasis. Overall, 11 RCTs were included for meta-analyses and network meta-analyses (NMAs). We found that the triplet combinations outperformed DOC + ADT in terms of OS (pooled hazard ratio [HR]: 0.74, 95% confidence interval [CI]: 0.65–0.84) and PFS (pooled HR: 0.49, 95% CI: 0.42–0.58). There was no statistically significant difference between patients with low- and high-volume disease in terms of an OS benefit from adding an ARSI to DOC +ADT (both HR: 0.79; p = 1). Based on NMAs, triplet therapy also outperformed ARSI + ADT in terms of OS (DAR + DOC + ADT: pooled HR: 0.74, 95% CI: 0.55–0.99) and PFS (ABI + DOC + ADT: HR: 0.68, 95% CI: 0.51–0.91, and ENZ + DOC + ADT: HR: 0.70, 95% CI: 0.53–0.93). An analysis of treatment ranking among de novo mHSPC patients showed that triplet therapy had the highest likelihood of improved OS in patients with high-volume disease; however, doublet therapy using ARSI + ADT had the highest likelihood of improved OS in patients with low-volume disease. We found that the triplet combination therapy improves survival endpoints in mHSPC patients compared with currently available doublet treatment regimens. Our findings need to be confirmed in further head-to-head trials with longer follow-up and among various patient populations. Our study suggests that triplet therapy with androgen receptor signaling inhibitor, docetaxel, androgen deprivation therapy prolongs survival in patients with metastatic hormone-sensitive prostate cancer compared with the current standard doublet therapy.
The significance of spleen size in children with sickle cell anemia
Authors: Amina Nardo‐Marino, Andreas Glenthøj, John N. Brewin, Jesper Petersen, Thomas H. Braunstein, Jørgen A. L. Kurtzhals, Thomas N. Williams, David C. Rees
Journal: American Journal of Hematology (2022)

It is well established that splenic dysfunction occurs in early childhood in sickle cell anemia (SCA), although the determinants and consequences of splenic injury are not fully understood. In this study, we examined spleen size and splenic function in 100 children with SCA aged 0-16 years at King's College Hospital in London. Spleen size was assessed by abdominal ultrasound (US) and splenic function by pitted red blood cells (PIT counts). In our cohort, 5.6% of children aged 6-10 years and 19.4% of children aged 11-16 years had no visible spleen on US (autosplenectomy). Splenomegaly was common in all age groups, with 28% of children overall having larger spleens than the average for their age. Only one child had a PIT count suggesting preserved splenic function. We found no correlation between hemoglobin F levels and spleen size, nor was there any difference in spleen size between children treated with or without hydroxyurea. Although there was a trend toward increased spleen length in children with co-inherited α-thalassemia, this did not reach statistical significance. Finally, we found a strong association between erythrocyte deformability measured with oxygen gradient ektacytometry, spleen size, and PIT counts. In conclusion, our results do not agree with the general perception that most children with SCA undergo autosplenectomy within the first decade of life and indicate that loss of erythrocyte deformability contributes to loss of splenic filtration capacity in SCA, as well as phenotypical variations in spleen size.
<scp>G6PD</scp> deficiency in patients identified as female
Authors: Barbara J. Bain, Jane Myburgh, Kirstin Lund, Aristeidis Chaidos
Journal: American Journal of Hematology (2022)

The left image (both images ×100 objective) is the blood film of a 3-year-old Syrian girl who presented with acute hemolysis 3 days after eating falafel. Her blood count showed a hemoglobin concentration (Hb) of 74 g/L and an MCHC of 375 g/L. The image shows irregularly contracted cells and numerous "blister cells" or "hemighosts." In addition, there is one cell that is virtually devoid of hemoglobin, a "ghost cell." G6PD was 2.2 U/gHb (normal range 6.3–11.2). The increased MCHC reflects the presence of numerous irregularly contracted cells. Because the hemolysis was unusually severe for a female, DNA analysis was performed. This showed homozygosity for G6PD c.653C>T; p.Ser218Phe, also known as G6PD Mediterranean. The patient's 5-year-old brother presented simultaneously with an Hb of 70 g/L and a G6PD assay of 2 U/gHb. The patient's father, who was known to be G6PD deficient, had milder haemolysis. Falafel are traditional made with chick peas but are sometimes made with fava beans (broad beans) or with a mixture of the two. Patients and physicians may not be aware of this possibility. The right image is of the blood film of an adult South Asian patient identified in hospital records as "female," who presented with fever and symptomatic anemia. It shows similar features to the first patient with numerous irregularly contracted cells and blister cells. In addition, Heinz bodies are apparent, precipitated within the otherwise empty area of cytoplasm within blister cells. Hb was 70 g/L. A G6PD assay confirmed deficiency. Again, the hemolysis was unusually severe for a female and further enquiries were made. It was discovered that the patient was a trans female, genetically male but choosing to identify in medical records as female. Other circumstances in which G6PD deficiency leading to symptomatic hemolysis of unexpected severity in a female that have been reported include Turner syndrome (female patients with a single X chromosome) and females who have been transplanted with bone marrow from a G6PD-deficient male. As it becomes possible in various jurisdictions for trans persons to legally change their gender in official records, diagnostic conundrums are likely to arise. Close liaison between clinical and laboratory staff is essential for these patients and also for those who have had a bone marrow transplant that is unknown to the laboratory as it was performed in another hospital. The authors declare no conflict of interest. Data availability statement is not applicable.
Expanding role for pharmacists.
Journal: BMJ (1978)

suggest that this discrepancy may be due to our Japanese patients having "concomitant medical problems" or "taking various medications"leading surprisingly to a normal CO2 response.To explain their own observations Dr Griffith and his colleagues suggest a functional disorder of the brain vessels in their hypertensive patients.Inhalation of CO2 in acute experimental hypertension causes an extreme rise in cerebral blood flow (CBF).'The finding of a normal rise in CBF in a hypertensive patient during CO, inhalation signifies structural and func- tional adaptation of the resistance vessels to the hypertensive state.This is analogous to the adaptation of CBF autoregulation to high blood pressure demonstrated in hypertensive patients.;The finding of a decreased response or even a decrease in CBF during CO2 inhalation, on the other hand, may be caused by stenosing atherosclerosis of the major brain vessels.Thus experimental carotid occlusion in the baboon diminishes the rise in CBF caused by CO2 inhalation by exhausting the arteriolar dilatatory capacity in the resting state.4Our Japanese patients had bilateral carotid angiography as part of their clinical investiga- tion and were included in the CO2 reactivity study only if no significant cerebral athero- sclerosis or other abnormality was present.Further, they were as a group somewhat younger than the patients of Dr Griffith and his colleagues (mean age 43 v 50 years), who were not investigated for atherosclerosis.It may also be mentioned that the extracerebral compartment of CBF, as measured by the 13'Xe-inhalation method used by them, would be expected to decrease during CO2 inhalation.Hypercapnia causes a generalised vasocon- striction (and thereby a rise in blood pressure) and has a dilatatory effect only in limited areas such as the cerebral and coronary circulations.In conclusion, the discrepancy between the results of Dr Griffith and his colleagues and our own may be due to more pronounced atherosclerosis in the British hypertensive patients or it may be due to differences in methodology.
Highlights of This Issue
Journal: Clinical Cancer Research (2018)

In the current landscape of cancer immunotherapy and targeted therapy, it is important to continue to evaluate strategies of improving delivery of chemotherapy while at the same time reducing its classic toxicity profile. In a phase 1 trial, Subbiah and colleagues evaluated a novel cisplatin nanoparticle developed using micellar technology in combination with gemcitabine in patients with advanced solid tumors. In the dose escalation phase, a Bayesian continual reassessment model to determine the optimal dose of NC-6004 was used. A greater cisplatin equivalent dose with no clinically significant neuro-, oto- or nephrotoxicity was achieved. Tolerability and early signals of promising activity was observed with the nanoparticle delivery of cisplatin.Metastatic disease in the central nervous system continues to be a major clinical challenge. CAR-based T-cell immunotherapy is being actively investigated for the treatment of solid tumors, including HER2+ breast cancers. Priceman and colleagues provide preclinical data that demonstrate effective targeting of breast cancer brain metastases with regional intraventricular delivery of T cells engineered with a HER2-CAR containing a 4-1BB intracellular costimulatory domain. The widespread application of this optimized CAR and the novel route of T-cell administration may impact CAR T-cell therapy for other HER2+ solid tumors and their brain metastases.Wang and colleagues reveal that the immunomodulatory drug lenalidomide augments the effectiveness of CAR T cells by several means, including mediating enhanced effector function and improving immune synapse formation between CAR T cells and targets, while maintaining a memory T-cell signature and increasing CAR T-cell persistence. The authors observed significantly improved antitumor activity of adoptively transferred CAR T cells in a multiple myeloma mouse model when this combination therapy was applied. These data suggest a viable strategy to boost the efficacy of CAR T cells against multiple myeloma and provide a generalizable approach for combining lenalidomide and CAR T cells.The use of anti-GD2 mAb as tumor-targeted immunotherapy has improved the outcome for high-risk neuroblastoma patients, but not all patients benefit from this immunotherapy. Prior clinical trials have demonstrated that genotypic polymorphisms specific to NK cells (KIR and KIR-ligand) are associated with clinical outcome. Erbe and colleagues evaluated KIR/KIR-ligand genotypes in patients from a randomized phase-III trial of anti-GD2-based immunotherapy and identified certain KIR/KIR-ligand genotypes that associated with improved outcome if patients received immunotherapy. These results confirm that NK cells mediate outcome in this clinical setting and could provide a biomarker for prospectively personalizing care.
A genetic model for central chondrosarcoma evolution correlates with patient outcome
Authors: William Cross, Iben Lyskjær, Tom Lesluyes, Steven Hargreaves, Anna-Christina Strobl, Christopher Davies, Sara Waise, Shadi Hames-Fathi, Dahmane Oukrif, Hongtao Ye, Fernanda Amary, Roberto Tirabosco, Craig Gerrand, Toby Baker, David Barnes, Christopher Steele, Ludmil Alexandrov, Gareth Bond, Paul Cool, Nischalan Pillay, Peter Van Loo, Adrienne M. Flanagan
Journal: Genome Medicine (2022)

Central conventional chondrosarcoma (CS) is the most common subtype of primary malignant bone tumour in adults. Treatment options are usually limited to surgery, and prognosis is challenging. These tumours are characterised by the presence and absence of IDH1 and IDH2 mutations, and recently, TERT promoter alterations have been reported in around 20% of cases. The effect of these mutations on clinical outcome remains unclear. The purpose of this study was to determine if prognostic accuracy can be improved by the addition of genomic data, and specifically by examination of IDH1, IDH2, and TERT mutations. In this study, we combined both archival samples and data sourced from the Genomics England 100,000 Genomes Project (n = 356). Mutations in IDH1, IDH2, and TERT were profiled using digital droplet PCR (n = 346), whole genome sequencing (n=68), or both (n = 64). Complex events and other genetic features were also examined, along with methylation array data (n = 84). We correlated clinical features and patient outcomes with our genetic findings. IDH2-mutant tumours occur in older patients and commonly present with high-grade or dedifferentiated disease. Notably, TERT mutations occur most frequently in IDH2-mutant tumours, although have no effect on survival in this group. In contrast, TERT mutations are rarer in IDH1-mutant tumours, yet they are associated with a less favourable outcome in this group. We also found that methylation profiles distinguish IDH1- from IDH2-mutant tumours. IDH wild-type tumours rarely exhibit TERT mutations and tend to be diagnosed in a younger population than those with tumours harbouring IDH1 and IDH2 mutations. A major genetic feature of this group is haploidisation and subsequent genome doubling. These tumours evolve less frequently to dedifferentiated disease and therefore constitute a lower risk group. Tumours with IDH1 or IDH2 mutations or those that are IDHwt have significantly different genetic pathways and outcomes in relation to TERT mutation. Diagnostic testing for IDH1, IDH2, and TERT mutations could therefore help to guide clinical monitoring and prognostication.
Manifestations of Coronary Disease Predisposing to Stroke
Authors: William B. Kannel
Journal: JAMA (1983)

Coronary heart disease (CHD) was examined as a precursor of stroke based on 24 years of biennial examinations, during which time 344 strokes occurred. Routine ECGs, chest roentgenograms, and BP levels were obtained, CHD and cardiac failure status were evaluated at each examination, and risk of stroke was ascertained. The five major CHD risk factors jointly were actually as predictive of stroke as CHD. The dominant stroke risk factors were hypertension, clinical manifestations of CHD, cardiac failure, atrial fibrillation, and ECG and roentgenographic evidence of a compromised coronary circulation. Coronary heart disease almost tripled the risk of a stroke, and cardiac failure was associated with more than a fivefold increased risk. Angina pectoris carried half the risk of myocardial infarction. Coronary disease and cardiac failure added to the risk of stroke associated with hypertension. Coronary heart disease increased stroke risk in the absence of hypertension or cardiac failure, but risk was greatly augmented when these coexisted. (<i>JAMA</i>1983;250:2942-2946)
CLINICAL HISTORY OF THE CASE OF PRESIDENT JAMES ABRAM GARFIELD.
Authors: ROBERT REYBURN
Journal: JAMA (1894)

(Continued from page 417). July 7, 2:30P.M.The President vomited twice this morning, and complains of acidity of the stomach. Powders containing each fifteen grains of bicarbonate of soda were given him, and the surface of his body thoroughly and frequently sponged off. Temperature 101.4; pulse 108; respirations 24. July 7, 8 to 11:30P.M.He asked for the hypodermatic injection at 8P.M., and slept until 11P.M.He then awoke suffering very much from pain in his ankles. Some solution of bromid of potassium was sent for, but he fell asleep before it could be administered. Temp. 100.2; pulse 106; respirations 23. July 8, 8:15A.M.The President slept well during the night, and awoke at 6:30A.M., in good spirits. Wound dressed antiseptically at 8:15A.M.A slight slough separating from edges of wound with laudable pus. Very little inflammation around edges of wound. At 8
An Atlas of the Commoner Skin Diseases
Journal: JAMA (1935)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Cerebrovascular Disease
Journal: JAMA (1998)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Musculoskeletal Disorders
Journal: JAMA (2000)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal